Login Register Cart 0
Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Structure-property Relationships Reported for the New Drugs Approved in 2022

Author(s): Kihang Choi*

Volume 24, Issue 3, 2024

Published on: 12 June, 2023

Page: [330 - 340] Pages: 11

DOI: 10.2174/1389557523666230519162803

Price: $65

Abstract

Background: The structure–property relationship illustrates how modifying the chemical structure of a pharmaceutical compound influences its absorption, distribution, metabolism, excretion, and other related properties. Understanding structure–property relationships of clinically approved drugs could provide useful information for drug design and optimization strategies.

Method: Among new drugs approved around the world in 2022, including 37 in the US, structure– property relationships of seven drugs were compiled from medicinal chemistry literature, in which detailed pharmacokinetic and/or physicochemical properties were disclosed not only for the final drug but also for its key analogues generated during drug development.

Results: The discovery campaigns for these seven drugs demonstrate extensive design and optimization efforts to identify suitable candidates for clinical development. Several strategies have been successfully employed, such as attaching a solubilizing group, bioisosteric replacement, and deuterium incorporation, resulting in new compounds with enhanced physicochemical and pharmacokinetic properties.

Conclusion: The structure-property relationships hereby summarized illustrate how proper structural modifications could successfully improve the overall drug-like properties. The structure–property relationships of clinically approved drugs are expected to continue to provide valuable references and guides for the development of future drugs.

Keywords: Structure-property relationship, solubilizing group, deuterium incorporation, lead optimization, candidate selection, drug discovery.

« Previous Next »
Graphical Abstract

[1]
Khanna, I. Drug discovery in pharmaceutical industry: Productivity challenges and trends. Drug Discov. Today, 2012, 17(19-20), 1088-1102.
[http://dx.doi.org/10.1016/j.drudis.2012.05.007] [PMID: 22627006]
[2]
Smith, G.F. Designing drugs to avoid toxicity. In: Progress in Medicinal Chemistry; Lawton, G.; Witty, D.R., Eds.; Elsevier, 2011; 50, p. 1-47.
[http://dx.doi.org/10.1016/B978-0-12-381290-2.00001-X]
[3]
Kalgutkar, A.S. Designing around structural alerts in drug discovery. J. Med. Chem., 2020, 63(12), 6276-6302.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00917] [PMID: 31497963]
[4]
Stepan, A.F.; Mascitti, V.; Beaumont, K.; Kalgutkar, A.S. Metabolism-guided drug design. Med. Chem. Comm., 2013, 4(4), 631-652.
[http://dx.doi.org/10.1039/c2md20317k]
[5]
Shanu-Wilson, J.; Evans, L.; Wrigley, S.; Steele, J.; Atherton, J.; Boer, J. Biotransformation: Impact and application of metabolism in drug discovery. ACS Med. Chem. Lett., 2020, 11(11), 2087-2107.
[http://dx.doi.org/10.1021/acsmedchemlett.0c00202] [PMID: 33214818]
[6]
Driscoll, J.P.; Sadlowski, C.M.; Shah, N.R.; Feula, A. Metabolism and bioactivation: It’s time to expect the unexpected. J. Med. Chem., 2020, 63(12), 6303-6314.
[http://dx.doi.org/10.1021/acs.jmedchem.0c00026] [PMID: 32267691]
[7]
Cerny, M.A.; Kalgutkar, A.S.; Obach, R.S.; Sharma, R.; Spracklin, D.K.; Walker, G.S. Effective application of metabolite profiling in drug design and discovery. J. Med. Chem., 2020, 63(12), 6387-6406.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01840] [PMID: 32097005]
[8]
Gajula, S.N.R.; Nadimpalli, N.; Sonti, R. Drug metabolic stability in early drug discovery to develop potential lead compounds. Drug Metab. Rev., 2021, 53(3), 459-477.
[http://dx.doi.org/10.1080/03602532.2021.1970178] [PMID: 34406889]
[9]
Korfmacher, W. Advances in the integration of drug metabolism into the lead optimization paradigm. Mini Rev. Med. Chem., 2009, 9(6), 703-716.
[http://dx.doi.org/10.2174/138955709788452694] [PMID: 19519496]
[10]
Weaver, R.J.; Blomme, E.A.; Chadwick, A.E.; Copple, I.M.; Gerets, H.H.J.; Goldring, C.E.; Guillouzo, A.; Hewitt, P.G.; Ingelman-Sundberg, M.; Jensen, K.G.; Juhila, S.; Klingmüller, U.; Labbe, G.; Liguori, M.J.; Lovatt, C.A.; Morgan, P.; Naisbitt, D.J.; Pieters, R.H.H.; Snoeys, J.; van de Water, B.; Williams, D.P.; Park, B.K. Managing the challenge of drug-induced liver injury: A roadmap for the development and deployment of preclinical predictive models. Nat. Rev. Drug Discov., 2020, 19(2), 131-148.
[http://dx.doi.org/10.1038/s41573-019-0048-x] [PMID: 31748707]
[11]
Yokoi, T.; Oda, S. Models of idiosyncratic drug-induced liver injury. Annu. Rev. Pharmacol. Toxicol., 2021, 61(1), 247-268.
[http://dx.doi.org/10.1146/annurev-pharmtox-030220-015007] [PMID: 32976738]
[12]
Mignani, S.; Huber, S.; Tomás, H.; Rodrigues, J.; Majoral, J.P. Why and how have drug discovery strategies in pharma changed? What are the new mindsets? Drug Discov. Today, 2016, 21(2), 239-249.
[http://dx.doi.org/10.1016/j.drudis.2015.09.007] [PMID: 26376356]
[13]
Chi, L.H.; Burrows, A.D.; Anderson, R.L. Can preclinical drug development help to predict adverse events in clinical trials? Drug Discov. Today, 2022, 27(1), 257-268.
[http://dx.doi.org/10.1016/j.drudis.2021.08.010] [PMID: 34469805]
[14]
Bowes, J.; Brown, A.J.; Hamon, J.; Jarolimek, W.; Sridhar, A.; Waldron, G.; Whitebread, S. Reducing safety-related drug attrition: The use of in vitro pharmacological profiling. Nat. Rev. Drug Discov., 2012, 11(12), 909-922.
[http://dx.doi.org/10.1038/nrd3845] [PMID: 23197038]
[15]
La Rochelle, P.; Lexchin, J.; Simonyan, D. Analysis of the drugs withdrawn from the US market from 1976 to 2010 for safety reasons. Pharmaceut. Med., 2016, 30(5), 277-289.
[http://dx.doi.org/10.1007/s40290-016-0159-1]
[16]
Harrison, R.K. Phase II and phase III failures: 2013–2015. Nat. Rev. Drug Discov., 2016, 15(12), 817-818.
[http://dx.doi.org/10.1038/nrd.2016.184] [PMID: 27811931]
[17]
Boyer, S.; Brealey, C.; Davis, A.M. Attrition in drug discovery and development. In: Attrition in the Pharmaceutical Industry; Alex, A.; Harris, C.J.; Smith, D.A., Eds.; John Wiley & Sons, 2015; pp. 5-45.
[http://dx.doi.org/10.1002/9781118819586.ch1]
[18]
Sun, D.; Gao, W.; Hu, H.; Zhou, S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm. Sin. B, 2022, 12(7), 3049-3062.
[http://dx.doi.org/10.1016/j.apsb.2022.02.002] [PMID: 35865092]
[19]
Choi, K. The structure–property relationships of clinically approved protein kinase inhibitors. Curr. Med. Chem., 2023, 30(22), 2518-2541.
[http://dx.doi.org/10.2174/0929867329666220822123552] [PMID: 35996243]
[20]
Choi, K. The structure-property relationships of gpcr-targeted drugs approved between 2011 and 2021. Curr. Med. Chem., 2023, 30(31), 3527-3549.
[http://dx.doi.org/10.2174/1573399819666221102113217] [PMID: 36330638]
[21]
U.S. Food and Drug Administration. Novel drug approvals for, 2022. Available from: https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2022
[22]
Mullard, A. FDA approvals. Nat. Rev. Drug Discov., 2023, 2023, 83-88.
[http://dx.doi.org/10.1038/d41573-023-00001-3] [PMID: 36596858]
[23]
Erlanson, D.A.; Webster, K.R. Targeting mutant KRAS. Curr. Opin. Chem. Biol., 2021, 62, 101-108.
[http://dx.doi.org/10.1016/j.cbpa.2021.02.010] [PMID: 33838397]
[24]
Fell, J.B.; Fischer, J.P.; Baer, B.R.; Ballard, J.; Blake, J.F.; Bouhana, K.; Brandhuber, B.J.; Briere, D.M.; Burgess, L.E.; Burkard, M.R.; Chiang, H.; Chicarelli, M.J.; Davidson, K.; Gaudino, J.J.; Hallin, J.; Hanson, L.; Hee, K.; Hicken, E.J.; Hinklin, R.J.; Marx, M.A.; Mejia, M.J.; Olson, P.; Savechenkov, P.; Sudhakar, N.; Tang, T.P.; Vigers, G.P.; Zecca, H.; Christensen, J.G. Discovery of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. ACS Med. Chem. Lett., 2018, 9(12), 1230-1234.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00382] [PMID: 30613331]
[25]
Fell, J.B.; Fischer, J.P.; Baer, B.R.; Blake, J.F.; Bouhana, K.; Briere, D.M.; Brown, K.D.; Burgess, L.E.; Burns, A.C.; Burkard, M.R.; Chiang, H.; Chicarelli, M.J.; Cook, A.W.; Gaudino, J.J.; Hallin, J.; Hanson, L.; Hartley, D.P.; Hicken, E.J.; Hingorani, G.P.; Hinklin, R.J.; Mejia, M.J.; Olson, P.; Otten, J.N.; Rhodes, S.P.; Rodriguez, M.E.; Savechenkov, P.; Smith, D.J.; Sudhakar, N.; Sullivan, F.X.; Tang, T.P.; Vigers, G.P.; Wollenberg, L.; Christensen, J.G.; Marx, M.A. Identification of the clinical development candidate MRTX849, a covalent KRASG12C inhibitor for the treatment of cancer. J. Med. Chem., 2020, 63(13), 6679-6693.
[http://dx.doi.org/10.1021/acs.jmedchem.9b02052] [PMID: 32250617]
[26]
Burke, J.R.; Cheng, L.; Gillooly, K.M.; Strnad, J.; Zupa-Fernandez, A.; Catlett, I.M.; Zhang, Y.; Heimrich, E.M.; McIntyre, K.W.; Cunningham, M.D.; Carman, J.A.; Zhou, X.; Banas, D.; Chaudhry, C.; Li, S.; D’Arienzo, C.; Chimalakonda, A.; Yang, X.; Xie, J.H.; Pang, J.; Zhao, Q.; Rose, S.M.; Huang, J.; Moslin, R.M.; Wrobleski, S.T.; Weinstein, D.S.; Salter-Cid, L.M. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Sci. Transl. Med., 2019, 11(502), eaaw1736.
[http://dx.doi.org/10.1126/scitranslmed.aaw1736]
[27]
Moslin, R.; Zhang, Y.; Wrobleski, S.T.; Lin, S.; Mertzman, M.; Spergel, S.; Tokarski, J.S.; Strnad, J.; Gillooly, K.; McIntyre, K.W.; Zupa-Fernandez, A.; Cheng, L.; Sun, H.; Chaudhry, C.; Huang, C.; D’Arienzo, C.; Heimrich, E.; Yang, X.; Muckelbauer, J.K.; Chang, C.; Tredup, J.; Mulligan, D.; Xie, D.; Aranibar, N.; Chiney, M.; Burke, J.R.; Lombardo, L.; Carter, P.H.; Weinstein, D.S. Identification of N-methyl nicotinamide and N-methyl pyridazine-3-carboxamide pseudokinase domain ligands as highly selective allosteric inhibitors of tyrosine kinase 2 (TYK2). J. Med. Chem., 2019, 62(20), 8953-8972.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00443] [PMID: 31314518]
[28]
Hall, L.R.; Hanzlik, R.P. Kinetic deuterium isotope effects on the N-demethylation of tertiary amides by cytochrome P-450. J. Biol. Chem., 1990, 265(21), 12349-12355.
[http://dx.doi.org/10.1016/S0021-9258(19)38353-X] [PMID: 2373695]
[29]
Guengerich, F.P. Kinetic deuterium isotope effects in cytochrome P450 reactions. Methods Enzymol., 2017, 596, 217-238.
[http://dx.doi.org/10.1016/bs.mie.2017.06.036] [PMID: 28911772]
[30]
Wrobleski, S.T.; Moslin, R.; Lin, S.; Zhang, Y.; Spergel, S.; Kempson, J.; Tokarski, J.S.; Strnad, J.; Zupa-Fernandez, A.; Cheng, L.; Shuster, D.; Gillooly, K.; Yang, X.; Heimrich, E.; McIntyre, K.W.; Chaudhry, C.; Khan, J.; Ruzanov, M.; Tredup, J.; Mulligan, D.; Xie, D.; Sun, H.; Huang, C.; D’Arienzo, C.; Aranibar, N.; Chiney, M.; Chimalakonda, A.; Pitts, W.J.; Lombardo, L.; Carter, P.H.; Burke, J.R.; Weinstein, D.S. Highly selective inhibition of tyrosine kinase 2 (TYK2) for the treatment of autoimmune diseases: Discovery of the allosteric inhibitor BMS-986165. J. Med. Chem., 2019, 62(20), 8973-8995.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00444] [PMID: 31318208]
[31]
Dowarah, J.; Singh, V.P. Anti-diabetic drugs recent approaches and advancements. Bioorg. Med. Chem., 2020, 28(5), 115263.
[http://dx.doi.org/10.1016/j.bmc.2019.115263] [PMID: 32008883]
[32]
Zhang, Y.; Liu, Z.P. Recent developments of C-aryl glucoside SGLT2 inhibitors. Curr. Med. Chem., 2016, 23(8), 832-849.
[http://dx.doi.org/10.2174/0929867323666160210125747] [PMID: 26861002]
[33]
Kong, Y.K.; Song, K.S.; Jung, M.E.; Kang, M.; Kim, H.J.; Kim, M.J. Discovery of GCC5694A: A potent and selective sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes. Bioorg. Med. Chem. Lett., 2022, 56, 128466.
[http://dx.doi.org/10.1016/j.bmcl.2021.128466] [PMID: 34813882]
[34]
Meng, W.; Ellsworth, B.A.; Nirschl, A.A.; McCann, P.J.; Patel, M.; Girotra, R.N.; Wu, G.; Sher, P.M.; Morrison, E.P.; Biller, S.A.; Zahler, R.; Deshpande, P.P.; Pullockaran, A.; Hagan, D.L.; Morgan, N.; Taylor, J.R.; Obermeier, M.T.; Humphreys, W.G.; Khanna, A.; Discenza, L.; Robertson, J.G.; Wang, A.; Han, S.; Wetterau, J.R.; Janovitz, E.B.; Flint, O.P.; Whaley, J.M.; Washburn, W.N. Discovery of dapagliflozin: A potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem., 2008, 51(5), 1145-1149.
[http://dx.doi.org/10.1021/jm701272q] [PMID: 18260618]
[35]
Choi, M.K.; Nam, S.J.; Ji, H.Y.; Park, M.J.; Choi, J.S.; Song, I.S. Comparative pharmacokinetics and pharmacodynamics of a novel sodium-glucose cotransporter 2 inhibitor, DWP16001, with dapagliflozin and ipragliflozin. Pharmaceutics, 2020, 12(3), 268.
[http://dx.doi.org/10.3390/pharmaceutics12030268] [PMID: 32183468]
[36]
Ullrich, S.; Nitsche, C. The SARS-CoV-2 main protease as drug target. Bioorg. Med. Chem. Lett., 2020, 30(17), 127377.
[http://dx.doi.org/10.1016/j.bmcl.2020.127377] [PMID: 32738988]
[37]
Cannalire, R.; Cerchia, C.; Beccari, A.R.; Di Leva, F.S.; Summa, V. Targeting SARS-CoV-2 proteases and polymerase for COVID-19 treatment: State of the art and future opportunities. J. Med. Chem., 2022, 65(4), 2716-2746.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01140] [PMID: 33186044]
[38]
Hoffman, R.L.; Kania, R.S.; Brothers, M.A.; Davies, J.F.; Ferre, R.A.; Gajiwala, K.S.; He, M.; Hogan, R.J.; Kozminski, K.; Li, L.Y.; Lockner, J.W.; Lou, J.; Marra, M.T.; Mitchell, L.J., Jr; Murray, B.W.; Nieman, J.A.; Noell, S.; Planken, S.P.; Rowe, T.; Ryan, K.; Smith, G.J., III; Solowiej, J.E.; Steppan, C.M.; Taggart, B. Discovery of ketone-based covalent inhibitors of coronavirus 3CL proteases for the potential therapeutic treatment of COVID-19. J. Med. Chem., 2020, 63(21), 12725-12747.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01063] [PMID: 33054210]
[39]
Owen, D.R.; Allerton, C.M.N.; Anderson, A.S.; Aschenbrenner, L.; Avery, M.; Berritt, S.; Boras, B.; Cardin, R.D.; Carlo, A.; Coffman, K.J.; Dantonio, A.; Di, L.; Eng, H.; Ferre, R.; Gajiwala, K.S.; Gibson, S.A.; Greasley, S.E.; Hurst, B.L.; Kadar, E.P.; Kalgutkar, A.S.; Lee, J.C.; Lee, J.; Liu, W.; Mason, S.W.; Noell, S.; Novak, J.J.; Obach, R.S.; Ogilvie, K.; Patel, N.C.; Pettersson, M.; Rai, D.K.; Reese, M.R.; Sammons, M.F.; Sathish, J.G.; Singh, R.S.P.; Steppan, C.M.; Stewart, A.E.; Tuttle, J.B.; Updyke, L.; Verhoest, P.R.; Wei, L.; Yang, Q.; Zhu, Y. An oral SARS-CoV-2 M pro inhibitor clinical candidate for the treatment of COVID-19. Science, 2021, 374(6575), 1586-1593.
[http://dx.doi.org/10.1126/science.abl4784] [PMID: 34726479]
[40]
Konno, S.; Thanigaimalai, P.; Yamamoto, T.; Nakada, K.; Kakiuchi, R.; Takayama, K.; Yamazaki, Y.; Yakushiji, F.; Akaji, K.; Kiso, Y.; Kawasaki, Y.; Chen, S.E.; Freire, E.; Hayashi, Y. Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety. Bioorg. Med. Chem., 2013, 21(2), 412-424.
[http://dx.doi.org/10.1016/j.bmc.2012.11.017] [PMID: 23245752]
[41]
Pirozzi, C.J.; Yan, H. The implications of IDH mutations for cancer development and therapy. Nat. Rev. Clin. Oncol., 2021, 18(10), 645-661.
[http://dx.doi.org/10.1038/s41571-021-00521-0] [PMID: 34131315]
[42]
Lin, J.; Lu, W.; Caravella, J.A.; Campbell, A.M.; Diebold, R.B.; Ericsson, A.; Fritzen, E.; Gustafson, G.R.; Lancia, D.R., Jr; Shelekhin, T.; Wang, Z.; Castro, J.; Clarke, A.; Gotur, D.; Josephine, H.R.; Katz, M.; Diep, H.; Kershaw, M.; Yao, L.; Kauffman, G.; Hubbs, S.E.; Luke, G.P.; Toms, A.V.; Wang, L.; Bair, K.W.; Barr, K.J.; Dinsmore, C.; Walker, D.; Ashwell, S. Discovery and optimization of quinolinone derivatives as potent, selective, and orally bioavailable mutant isocitrate dehydrogenase 1 (MIDH1) inhibitors. J. Med. Chem., 2019, 62(14), 6575-6596.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00362] [PMID: 31199148]
[43]
Caravella, J.A.; Lin, J.; Diebold, R.B.; Campbell, A.M.; Ericsson, A.; Gustafson, G.; Wang, Z.; Castro, J.; Clarke, A.; Gotur, D.; Josephine, H.R.; Katz, M.; Kershaw, M.; Yao, L.; Toms, A.V.; Barr, K.J.; Dinsmore, C.J.; Walker, D.; Ashwell, S.; Lu, W. Structure-based design and identification of FT-2102 (olutasidenib), a potent mutant-selective IDH1 inhibitor. J. Med. Chem., 2020, 63(4), 1612-1623.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01423] [PMID: 31971798]
[44]
William, A.D.; Lee, A.C.H.; Blanchard, S.; Poulsen, A.; Teo, E.L.; Nagaraj, H.; Tan, E.; Chen, D.; Williams, M.; Sun, E.T.; Goh, K.C.; Ong, W.C.; Goh, S.K.; Hart, S.; Jayaraman, R.; Pasha, M.K.; Ethirajulu, K.; Wood, J.M.; Dymock, B.W. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J. Med. Chem., 2011, 54(13), 4638-4658.
[http://dx.doi.org/10.1021/jm200326p] [PMID: 21604762]
[45]
Poulsen, A.; William, A.; Blanchard, S.; Lee, A.; Nagaraj, H.; Wang, H.; Teo, E.; Tan, E.; Goh, K.C.; Dymock, B. Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3). J. Comput. Aided Mol. Des., 2012, 26(4), 437-450.
[http://dx.doi.org/10.1007/s10822-012-9572-z] [PMID: 22527961]
[46]
Hart, S.; Goh, K.C.; Novotny-Diermayr, V.; Hu, C.Y.; Hentze, H.; Tan, Y.C.; Madan, B.; Amalini, C.; Loh, Y.K.; Ong, L.C.; William, A.D.; Lee, A.; Poulsen, A.; Jayaraman, R.; Ong, K.H.; Ethirajulu, K.; Dymock, B.W.; Wood, J.W. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia, 2011, 25(11), 1751-1759.
[http://dx.doi.org/10.1038/leu.2011.148] [PMID: 21691275]
[47]
Jayaraman, R.; Pasha, M.; Williams, A.; Goh, K.; Ethirajulu, K. Metabolism and disposition of pacritinib (SB1518), an orally active Janus kinase 2 inhibitor in preclinical species and humans. Drug Metab. Lett., 2015, 9(1), 28-47.
[http://dx.doi.org/10.2174/1872312809666150119105250] [PMID: 25600203]
[48]
Shawky, A.M.; Almalki, F.A.; Abdalla, A.N.; Abdelazeem, A.H.; Gouda, A.M. A comprehensive overview of globally approved JAK inhibitors. Pharmaceutics, 2022, 14(5), 1001.
[http://dx.doi.org/10.3390/pharmaceutics14051001] [PMID: 35631587]
[49]
Li, L.; Wang, L.; You, Q.D.; Xu, X.L. Heat shock protein 90 inhibitors: An update on achievements, challenges, and future directions. J. Med. Chem., 2020, 63(5), 1798-1822.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00940] [PMID: 31663736]
[50]
Wang, L.; Zhang, Q.; You, Q. Targeting the HSP90–CDC37–kinase chaperone cycle: A promising therapeutic strategy for cancer. Med. Res. Rev., 2022, 42(1), 156-182.
[http://dx.doi.org/10.1002/med.21807] [PMID: 33846988]
[51]
Patil, V.M.; Masand, N.; Gupta, S.P.; Blagg, B.S.J. QSAR studies to predict activity of HSP90 inhibitors. Curr. Top. Med. Chem., 2021, 21(25), 2272-2291.
[http://dx.doi.org/10.2174/1568026621666211011095858] [PMID: 34635040]
[52]
Uno, T.; Kawai, Y.; Yamashita, S.; Oshiumi, H.; Yoshimura, C.; Mizutani, T.; Suzuki, T.; Chong, K.T.; Shigeno, K.; Ohkubo, M.; Kodama, Y.; Muraoka, H.; Funabashi, K.; Takahashi, K.; Ohkubo, S.; Kitade, M. Discovery of 3-Ethyl-4-(3-isopropyl-4-(4-(1-methyl-1 H -pyrazol-4-yl)-1 H -imidazol-1-yl)-1 H -pyrazolo[3,4- b]pyridin-1-yl)benzamide (TAS-116) as a potent, selective, and orally available HSP90 inhibitor. J. Med. Chem., 2019, 62(2), 531-551.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01085] [PMID: 30525599]
[53]
Huang, K.H.; Veal, J.M.; Fadden, R.P.; Rice, J.W.; Eaves, J.; Strachan, J.P.; Barabasz, A.F.; Foley, B.E.; Barta, T.E.; Ma, W.; Silinski, M.A.; Hu, M.; Partridge, J.M.; Scott, A.; DuBois, L.G.; Freed, T.; Steed, P.M.; Ommen, A.J.; Smith, E.D.; Hughes, P.F.; Woodward, A.R.; Hanson, G.J.; McCall, W.S.; Markworth, C.J.; Hinkley, L.; Jenks, M.; Geng, L.; Lewis, M.; Otto, J.; Pronk, B.; Verleysen, K.; Hall, S.E. Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents. J. Med. Chem., 2009, 52(14), 4288-4305.
[http://dx.doi.org/10.1021/jm900230j] [PMID: 19552433]
[54]
Rajan, A.; Kelly, R.J.; Trepel, J.B.; Kim, Y.S.; Alarcon, S.V.; Kummar, S.; Gutierrez, M.; Crandon, S.; Zein, W.M.; Jain, L.; Mannargudi, B.; Figg, W.D.; Houk, B.E.; Shnaidman, M.; Brega, N.; Giaccone, G. A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas. Clin. Cancer Res., 2011, 17(21), 6831-6839.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-0821] [PMID: 21908572]
[55]
Zhao, D.; Xu, Y.M.; Cao, L.Q.; Yu, F.; Zhou, H.; Qin, W.; Li, H.J.; He, C.X.; Xing, L.; Zhou, X.; Li, P.Q.; Jin, X.; He, Y.; He, J.H.; Cao, H.L. Complex crystal structure determination and in vitro anti–non–small cell lung cancer activity of Hsp90N inhibitor SNX-2112. Front. Cell Dev. Biol., 2021, 9, 650106.
[http://dx.doi.org/10.3389/fcell.2021.650106] [PMID: 33855025]
[56]
Ohkubo, S.; Kodama, Y.; Muraoka, H.; Hitotsumachi, H.; Yoshimura, C.; Kitade, M.; Hashimoto, A.; Ito, K.; Gomori, A.; Takahashi, K.; Shibata, Y.; Kanoh, A.; Yonekura, K. TAS-116, a highly selective inhibitor of heat shock protein 90α and β, demonstrates potent antitumor activity and minimal ocular toxicity in preclinical models. Mol. Cancer Ther., 2015, 14(1), 14-22.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0219] [PMID: 25416789]
[57]
Ishikawa, M.; Hashimoto, Y. Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry. J. Med. Chem., 2011, 54(6), 1539-1554.
[http://dx.doi.org/10.1021/jm101356p] [PMID: 21344906]
[58]
Ishikawa, M.; Hashimoto, Y. Improving the water-solubility of compounds by molecular modification to disrupt crystal packing. In: The Practice of Medicinal Chemistry, 4th ed; Academic Press, 2015; pp. 747-765.
[http://dx.doi.org/10.1016/B978-0-12-417205-0.00031-6]
[59]
Walker, M.A. Improvement in aqueous solubility achieved via small molecular changes. Bioorg. Med. Chem. Lett., 2017, 27(23), 5100-5108.
[http://dx.doi.org/10.1016/j.bmcl.2017.09.041] [PMID: 29100802]
[60]
Das, B.; Baidya, A.T.K.; Mathew, A.T.; Yadav, A.K.; Kumar, R. Structural modification aimed for improving solubility of lead compounds in early phase drug discovery. Bioorg. Med. Chem., 2022, 56, 116614.
[http://dx.doi.org/10.1016/j.bmc.2022.116614] [PMID: 35033884]
[61]
Blair, H.A. Fedratinib: First approval. Drugs, 2019, 79(15), 1719-1725.
[http://dx.doi.org/10.1007/s40265-019-01205-x] [PMID: 31571162]
[62]
Guagnano, V.; Furet, P.; Spanka, C.; Bordas, V.; Le Douget, M.; Stamm, C.; Brueggen, J.; Jensen, M.R.; Schnell, C.; Schmid, H.; Wartmann, M.; Berghausen, J.; Drueckes, P.; Zimmerlin, A.; Bussiere, D.; Murray, J.; Graus Porta, D. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J. Med. Chem., 2011, 54(20), 7066-7083.
[http://dx.doi.org/10.1021/jm2006222] [PMID: 21936542]
[63]
Gant, T.G. Using deuterium in drug discovery: Leaving the label in the drug. J. Med. Chem., 2014, 57(9), 3595-3611.
[http://dx.doi.org/10.1021/jm4007998] [PMID: 24294889]
[64]
Atzrodt, J.; Derdau, V.; Kerr, W.J.; Reid, M. Deuterium- and tritium-labelled compounds: Applications in the life sciences. Angew. Chem. Int. Ed., 2018, 57(7), 1758-1784.
[http://dx.doi.org/10.1002/anie.201704146] [PMID: 28815899]
[65]
Pirali, T.; Serafini, M.; Cargnin, S.; Genazzani, A.A. Applications of deuterium in medicinal chemistry. J. Med. Chem., 2019, 62(11), 5276-5297.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01808] [PMID: 30640460]
[66]
Schmidt, C. First deuterated drug approved. Nat. Biotechnol., 2017, 35(6), 493-494.
[http://dx.doi.org/10.1038/nbt0617-493] [PMID: 28591114]
[67]
Zhong, L.; Hou, C.; Zhang, L.; Zhao, J.; Li, F.; Li, W. Synthesis of deuterium-enriched sorafenib derivatives and evaluation of their biological activities. Mol. Divers., 2019, 23(2), 341-350.
[http://dx.doi.org/10.1007/s11030-018-9875-7] [PMID: 30238393]
[68]
Keam, S.J.; Duggan, S. Donafenib: First approval. Drugs, 2021, 81(16), 1915-1920.
[http://dx.doi.org/10.1007/s40265-021-01603-0] [PMID: 34591285]
[69]
Mullard, A. First de novo deuterated drug poised for approval. Nat. Rev. Drug Discov., 2022, 21(9), 623-625.
[http://dx.doi.org/10.1038/d41573-022-00139-6] [PMID: 35974147]
[70]
Singh, J.; Petter, R.C.; Baillie, T.A.; Whitty, A. The resurgence of covalent drugs. Nat. Rev. Drug Discov., 2011, 10(4), 307-317.
[http://dx.doi.org/10.1038/nrd3410] [PMID: 21455239]
[71]
Mah, R.; Thomas, J.R.; Shafer, C.M. Drug discovery considerations in the development of covalent inhibitors. Bioorg. Med. Chem. Lett., 2014, 24(1), 33-39.
[http://dx.doi.org/10.1016/j.bmcl.2013.10.003] [PMID: 24314671]
[72]
Boike, L.; Henning, N.J.; Nomura, D.K. Advances in covalent drug discovery. Nat. Rev. Drug Discov., 2022, 21(12), 881-898.
[http://dx.doi.org/10.1038/s41573-022-00542-z] [PMID: 36008483]
[73]
Bonatto, V.; Lameiro, R.F.; Rocho, F.R.; Lameira, J.; Leitão, A.; Montanari, C.A. Nitriles: An attractive approach to the development of covalent inhibitors. RSC Med. Chem., 2023, 14(2), 210-217.
[http://dx.doi.org/10.1039/D2MD00204C]
[74]
Gai, C.; Harnor, S.J.; Zhang, S.; Cano, C.; Zhuang, C.; Zhao, Q. Advanced approaches of developing targeted covalent drugs. RSC Med. Chem., 2022, 13(12), 1460-1475.
[http://dx.doi.org/10.1039/D2MD00216G] [PMID: 36561076]
[75]
Singh, J. The ascension of targeted covalent inhibitors. J. Med. Chem., 2022, 65(8), 5886-5901.
[http://dx.doi.org/10.1021/acs.jmedchem.1c02134] [PMID: 35439421]

Rights & Permissions Print Cite
Article Metrics
49
2
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy